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ToxSci Advance Access originally published online on January 26, 2005
Toxicological Sciences 2005 85(1):647-656; doi:10.1093/toxsci/kfi095
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Toxicological Sciences vol. 85 no. 1 © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Impairment in Short-Term but Enhanced Long-Term Synaptic Potentiation and ERK Activation in Adult Hippocampal Area CA1 Following Developmental Thyroid Hormone Insufficiency*

L. Sui*, W. L. Anderson{dagger} and M. E. Gilbert{dagger},{ddagger},1

* National Research Council, Washington, DC 20001; {dagger} Neurotoxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711; and {ddagger} Department of Psychology, University of North Carolina, North Carolina 27599

Received December 8, 2004; accepted January 12, 2005

Thyroid hormones are critical for the development and maturation of the central nervous system. Insufficiency of thyroid hormones during development impairs performance on tasks of learning and memory that rely upon the hippocampus and impairs synaptic function in young hypothyroid animals. The present study was designed to determine if perturbations in synaptic function persist in adult euthyroid animals exposed developmentally to insufficient levels of hormone. Pre- and postnatal thyroid hormone insufficiency was induced by administration of 3 or 10 ppm propylthiouracil (PTU) to pregnant and lactating dams via the drinking water from gestation day (GD) 6 until postnatal day (PN) 30. This regimen produced a graded level of hormonal insufficiency in the dam and the offspring. Population spike and population excitatory postsynaptic potentials (EPSP) were recorded at the pyramidal cell layer and the stratum radiatum, respectively, in area CA1 of hippocampal slices from adult male offspring. PTU exposure increased baseline synaptic transmission, reduced paired-pulse facilitation, and increased the magnitude of the population spike long-term potentiation (LTP). Phosphorylation of the extracellular signal-regulated kinases (ERK1 and ERK2) was increased as a function of LTP stimulation in slices from PTU-exposed adult animals. On the other hand, no differences in the basal levels of synaptic proteins implicated in synaptic plasticity (total ERK, synapsin, growth-associated protein-43, and neurogranin) were detected. These results reinforce previous findings of persistent changes in synaptic function and, importantly extend these observations to moderate levels of thyroid hormone insufficiency that do not induce significant toxicity to the dams or the offspring. Such alterations in hippocampal synaptic function may contribute to persistent behavioral deficits associated with developmental hypothyroidism.

Key Words: hypothyroidism; hippocampus; paired-pulse facilitation; long-term potentiation; extracellular signal-regulated kinase; adult.


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